NMDA Receptors

Structure of the NMDA Receptor

Subunit Structure and splice variation

Figure 1. Structure of the NMDA receptor subunit, showing regions of splice variations. Roll over the boxes to see the different splice variants of the GluN1 subunit.

The NMDA receptor subunit has similar structural characteristics as other members of the ionotropic glutamate receptor family, with an extracellular N-terminus, intracellular C-terminus and a re-entrant transmembrane domain (Figure 1). There are two separate subunit families that go to make up the NMDA receptor, the GluN1and GluN2 subunits. The GluN1 subunit is an essential component of all NMDA receptor complexes while there are four GluN2 subunits (GluN2A-D) that are products of separate genes. GluN1 subunits are combined with different GluN2 subunits to generate a large number of different NMDA receptors with differing pharmacological and biological properties. Thus, NMDA receptors in different parts of the brain, or at different stages in development, may not act in the same way.

In addition to variation produced by the use of different GluN2 subunits in the receptor complex, the GluN1 subunit exists as multiple splice variants, produced by differential splicing of the mRNA derived from a single gene. There are two sites for splice variation, in the N-terminus and the C-terminus (roll over the indicated regions on Figure 1 for details). Such splice variation may be important in the regulation of intracellular interactions such as those with PDZ binding proteins such as PSD-95. A protein previously known as NMDAR-L has also recently been shown to be a NMDA receptor subunit, now termed GluN3A.

Glycine, Glutamate's co-agonist

Figure 2. Schematic for the structure of the NMDA receptor complex. The Glutamate binding domain is resident on the GluN2 subunit while the glycine co-agtonist binds within the GluN1 subunit

Unusually for the ionotropic glutamate receptors, L-glutamate is not the only agonist for the NMDA receptor. Glycine, another amino-acid, is a co-agonist and both transmitters must bind in order for the receptor to function. The binding sites for glutamate and glycine are found on different subunits - glycine binds to the GluN1 subunit while glutamate binds to the GluN2 subunit. This is one reason why both subunit types are required to generate a fully functioning receptor. The GluN2B subunit also posesses a binding site for ployamines, regulatory molecules that modulate the functioning of the NMDA receptor.

Function of the NMDA receptor

The NMDA receptor functions as a modulator of synaptic response and a co-incidence detector. At resting membrane potentials, NMDA receptors are inactive. This is due to a voltage-dependent block of the channel pore by magnesium ions, preventing ion flows through it. Sustained activation of AMPA receptors by, for instance, a train of impulses arriving at a pre-synaptic terminal, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDA receptor activation . Unlike GluA2-containing AMPA receptors, NMDA receptors are permeable to calcium ions as well as being permeable to other ions. Thus NMDA receptor activation leads to a calcium influx into the post-synaptic cells, a signal that is instrumental in the actvation of a number of signalling cascades. Depending on the specific impulse train received, the NMDA receptor is responsible for a wide range of post-synaptic functions:

activation of CaMKII and phosphorylation of the GluA2 AMPA receptor subunit resulting in LTP (HFS)

activation of PICK1 to drive the PKC-dependent synaptic insertion of AMPA receptors during LTP

activation of hippocalcin, a Ca2+-binding protein that recruits AP2 to the GluA2 AMPA receptor subunit prior to internalisation during LTD (LFS)